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Temsirolimus and pegylated liposomal doxorubicin (PLD) combination therapy in breast, endometrial, and ovarian cancer: phase Ib results and prediction of clinical outcome with FDG-PET/CT

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Abstract

Pegylated liposomal doxorubicin (PLD) is active in breast, endometrial, and ovarian cancer. Preclinical data suggest that the combination of PLD with a mammalian target of rapamycin (mTOR) inhibitor has an additive effect. The safety and recommended phase two dose (RPTD) of temsirolimus in combination with PLD were assessed. 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT was performed for early response monitoring. Nineteen patients with advanced breast, endometrial, and ovarian cancer were treated with increasing doses of temsirolimus (10, 15, or 20 mg once weekly) and PLD (30 or 40 mg/m2 once every 4 weeks). PLD was initiated 2 weeks after start of temsirolimus. FDG-PET/CT was performed at baseline, after 2 and 6 weeks. Standardized uptake values (SUV), metabolic volume, and total lesion glycolysis (TLG, SUV × metabolic volume) were calculated. The RPTD was 15 mg temsirolimus and 40 mg/m2 PLD. Dose-limiting toxicities (DLT) were thrombocytopenia grade 3 with nose bleeding and skin toxicity grade 3. Most frequent treatment-related toxicities were nausea, fatigue, mucositis, and skin toxicity. Changes in TLG after 2 weeks predicted partial response (PR) after 10 weeks (p = 0.037). A rise in SUV between the second and sixth week predicted progression (PD) (p = 0.034) and was associated with worse progression free survival (PFS) (HR 1.068; p = 0.013). The RPTD was established at 15 mg temsirolimus weekly and PLD 40 mg/m2 once every 4 weeks and the combination was safe. Early response evaluation with FDG-PET/CT may predict subsequent radiological PR and PD. This trial is registered under number NCT0098263.

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Funding

This work was supported by the manufacturers of temsirolimus and PLD: Wyeth Pharmaceuticals, Pfizer bv, Schering Plough, and Jansen-Cilag. These sponsors had no involvement in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

Conflict of interest

This work was supported by the manufacturers of temsirolimus and PLD: Wyeth Pharmaceuticals, Pfizer bv, Schering Plough, and Jansen-Cilag to CvH and NO. WdG has conducted preclinical studies supported by Pfizer bv and Wyeth pharmaceuticals, which also supported this study. All remaining authors have declared no conflicts of interest.

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Authors and Affiliations

  1. Department of Medical Oncology, Radboud UMC, PO Box 9101, 6500 HB, Nijmegen, The Netherlands

    Marye J. Boers-Sonderen, Ingrid M. E. Desar, Winette T. A. van der Graaf, Petronella B. Ottevanger & Carla M. L. van Herpen

  2. Department of Nuclear Medicine, Radboud UMC, Nijmegen, The Netherlands

    Lioe-Fee de Geus-Oei & Wim J. G. Oyen

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  1. Marye J. Boers-Sonderen
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  2. Lioe-Fee de Geus-Oei
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Correspondence to Marye J. Boers-Sonderen.

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Petronella B. Ottevanger and Carla M. L. van Herpen contributed equally to this manuscript.

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Boers-Sonderen, M.J., de Geus-Oei, LF., Desar, I.M.E. et al. Temsirolimus and pegylated liposomal doxorubicin (PLD) combination therapy in breast, endometrial, and ovarian cancer: phase Ib results and prediction of clinical outcome with FDG-PET/CT. Targ Oncol 9, 339–347 (2014). https://doi.org/10.1007/s11523-014-0309-x

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